PROJECT SUMMARY: Dermal scarring affects more than 80 million people worldwide annually - over 4.4 million people are injured in motor vehicle accidents, over 2.4 million patients are severely burned, and thousands of warriors are wounded in military blasts. In severe burns, more than 40% of patients develop hypertrophic scar contraction, which leads to hypertrophic scar contractures (HSc). HSc are stiff, shrunken scars that limit mobility, impact quality of life and cost millions of dollars per year in surgical treatment and physical therapy. HSc are caused by increased mechanical tension and occur 6-12 months after injury. Current tissue engineered scaffolds, such as IntegraTM, have mechanical properties akin to unwounded skin, but the collagen based scaffolds rapidly degrade over 2 months, being too short-lived to prevent HSc. The key to preventing HSc is having a biocompatible scaffold which degrades over 12 months. To achieve this goal, the development of scaffolds composed of viscoelastic copolymer, poly(?-lactide-co-?-caprolactone) (PLCL) is proposed. Published work has demonstrated that electrospun ~100 m thick PLCL scaffolds possess appropriate mechanical properties for implantation beneath skin grafts and inhibition of HSc in mice. However, electrospinning cannot be used to generate scaffolds at thickness necessary for large animal studies due to the great voltage gradient required for scaffold production. To overcome this hurdle solvent casting/particulate leaching (SCPL) will be used to create 3D porous PLCL scaffolds. This method involves the mixing of polymers with particles within an organic solvent followed by casting into a mold. Water is then passed through the mold to leach out the particles, resulting in an interconnected porous 3D scaffold. This SPCL method has successfully been used to create 2mm thick PLCL scaffolds, which have appropriate mechanical properties and tunable porosity for implantation beneath skin grafts. We hypothesize that optimized SCPL PLCL scaffolds will promote graft bioincorporation and dampen fibrosis in vivo. The three Aims to test our hypothesis are: Aim 1. Determine SCPL manufacturing parameters to create uniform PLCL scaffolds with controlled pore size, porosity, and mechanical properties. Aim 2. Determine the optimal porosity of collagen coated SCPL PLCL scaffolds for tissue ingrowth. Aim 3. Evaluate the safety and efficacy of optimal porosity PLCL scaffolds at promoting skin graft survival. The completion of these aims will validate a scalable method to create PLCL scaffolds and test them in rodent and swine wound models for safety and efficacy. The results will bring us closer toward developing an optimized technology that prevents HSc with the potential to improve millions of lives worldwide.